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Laboratory of Guillaume Lettre

Montreal Heart Institute | Université de Montréal

Université de Montréal Montréal Heart Institute
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The genetics of cardiovascular diseases

Cardiovascular diseases (CVDs) are the main cause of death in the Western world. In Canada, CVDs affect 1.3 million individuals and cost nearly $22 billions (direct and indirect costs) to the Canadian economy. Beyond the traditional risk factors (e.g. lipids, hypertension, obesity), familial history (genetics) is also predictive of an individual’s risk to develop CVDs. My laboratory uses high-throughput DNA genotyping and sequencing to identify and characterize new genes involved in atherosclerosis and other CVDs. We focus on the genetics of atherosclerosis-related complications (e.g. myocardial infarction) and relevant biomarkers (e.g. HDL-cholesterol efflux) using the large Biobank from the Montreal Heart Institute (N>17,000) and CARTaGÈNE (N>40,000). Through collaborations, my lab also has access to additional large datasets (UK Biobank, Canadian Longitudinal Study of Aging, NHLBI Exome Sequence Project and TOPMed).

 

Vascular endothelial cell genomics

Endothelial cells form the inner layer of blood vessels and play a critical role in maintaining cardiovascular health. They form a selective barrier, respond to inflammation, and control the vascular tone and hemostatic factors. We have developed a comprehensive program to characterize endothelial cells’ responses to different stimuli. It includes transcriptomic (RNA-sequencing), epigenomic (open chromatin regions, ATAC-sequencing) and chromosome conformation (Hi-C) changes. We are also using CRISPR/Cas9 genome editing screens to interrogate how genes and non-coding regulatory elements control endothelial cell functions.

Project Cell

 

Blood-cell production and differentiation (hematopoiesis)

Blood is mostly composed of plasma and blood cells and plays a major role in a variety of functions involved in general human homeostasis: it transports oxygen, nutrients and hormones to tissues, removes waste, performs immunological functions and contributes to tissue damage repair through coagulation. The main three blood cell types carry out most of these activities: red blood cells transport oxygen, white blood cells coordinate some of the immune responses, and platelets are the bricks that form blood clots to prevent excessive bleeding. All of these cell types originate through proliferation and differentiation from common precursors (hematopoietic stem cells). An aberrant number, size or feature of the three main blood cell types characterizes multiple human diseases (e.g. cancer, anemia, malaria, HIV). It is also known that blood-cell phenotypes vary between healthy individuals, and that some of this inter-individual variation is controlled by genetics. We created the international Blood-Cell Consortium to study in 1 million participants the genetic factors that control human hematopoiesis. We combine our genetic analyses with genomic (e.g. expression quantitative trait loci (eQTL)) and genome editing (e.g. CRISPR/Cas9) approaches to identify genes that regulate blood-cell parameters. Furthermore, we are also interested in exploring whether blood-cell phenotypes can be used as predictive biomarkers of hematological and cardiovascular diseases.

 

Clinical heterogeneity in sickle cell disease

Sickle cell disease (SCD) is one of the most common monogenic diseases in the world. It is particularly prevalent in countries where malaria is endemic, as carrying one copy of the SCD mutation confers protection from malaria infection. SCD presents an extremely heterogenous clinical course, with some patients being only mildly affected whereas others suffer devastating complications (e.g. stroke, renal failure). To understand this heterogeneity, we have been focusing on the genetic regulation of fetal hemoglobin levels, a strong modifier of SCD severity. We are now moving towards other phenotypes and measures of severity to further understand the pathophysiology of SCD. We are also interested in developing new therapies for SCD. For this project, we have access to large cohorts from the USA, France, and Africa.

 

Last Updated on Tuesday, 22 January 2019 16:06